dr. Mara Imam Taufiq Siregar, S.Pdi, M.

Biomed

DEPT. OF PHARMACOLOGY
FACULTY OF MEDICINE
JAMBI UNIVERSITY
JAMBI - 2015

Drugs used for immunomodulation

All drugs which modify immune response

generally categorized as immunomodulators.

These can either function as:

1. immunosupressants
2. immunostimulants

Basic concepts in Immunology

We live surrounded by
microorganism (viruses, fungi,
bacteria and parasites)
We become ill only relatively
rarely
Immune response against
pathogens (2 system)

Basic concepts in Immunology

Innate Immunity / inborn

Non-spesific defense against infection
Macrophages, Neutrophils
Its action does not depend on prior
exposure to a particular pathogens
Phagocytosis

Innate Immunity in pathogen elimination

Innate Immunity
Activate Complement system and they
will destroy the pathogen
Acute phase proteins produced by the
liver, stimulate the macrophage function
against infection
Those protein binds to bacterial surface
and activates complement system to
eliminate bacteria directly and enhance
their elimination by macrophages.

Innate Immunity

Secreted IL6 by the macrophage will

stimulate the liver to produce
acute phase proteins i.e :
C-reactive protein
Serum amyloid protein
Mannose binding protein
Fibrinogen

C-reactive protein
C-reactive protein binds to
Phosphorylcholine on bacterial surfaces
Mannose binding protein binds Mannosa
residu on bacterial surfaces
C-reactive protein and Mannose binding
protein respons like antibody
Opsonisation and activates the
complement cascade

Inflammatory response
Infection
bacteria trigger macrophages
to release inflammatory mediators.
Vasodilatation and increased vascular
permeability cause redness and heat (calor
dan rubor)
Leakage of cells and fluids cause swelling
and pain (dolor dan tumor)
Blood vessel walls become sticky allowing
blood cells to migrate into tissue.
T-cells activated by macrophages may
sustain chronic inflammation.

Basic concepts in Immunology

Acquired / Adaptive Immunity

Specific immunity
Acquired during the lifetime of an
individual
Response to a spesific pathogen
Lymphocytes (its receptors)
Antibodies

Immune System

Lymphatics System
Organs in Immune System
Central (Bone Marrow and Thymus)
Peripher (Adenoid, Tonsil, Peyers
Patches, Appendix, Spleen, Lymph
Nodes)
Thoracic duct
Right Subclavian Vein and Left
Subclavian vein

Growth factors in the Hematopoietic system

Act on proliferation and maturation of the
cells.
Secreted proteins termed Cytokines are
messenger molecules that can
communicate signals from one cell type to
another.
They can instruct the receiving cells to
proliferate, differentiate, secrete additional
cytokines, migrate or die.

Hematopoietic stem cells

The Bone marrow contains at least two
types of stem cells.
Mesenchymal stem cell which constitute
the bone marrow stroma and under
appropriate signals can differentiate into
adipocytes, osteocytes, chondrocytes and
myocytes
Hematopoietic stem cell which gives rise to
the formed elements of the blood and
produce growth factors including IL-3, -4,-6
and-7, G-CSF, GM-CSF, SCF, flt-3, EPO,
TPO, etc.

Cytokine families
They are able to support proliferation of
hematopoietic precursors (colony
stimulating factors)
Particular cytokine responses influence the
differentiation stage of the cell, its position
within the cell cycle (whether quiescent or
proliferating)
Cytokine action is transient and usually
short range

Clonal Selection of Lymphocytes

(Bone Marrow and Thymic gland)
single

type receptor on Lymphocytes

can recognize all possible antigens.
However, we normally do not make
immune responses against our own
tissues.
This is called Self Tolerance
Lymphocytes with receptors for self
antigens are eliminated (Clonal deletion)
Cell death occurs by Apoptosis

Clonal Selection of Lymphocytes

(Bone Marrow and Thymic gland)
The

remaining mature Lymphocytes

(naive lymphocytes) migrate to the
periphery.
Continuous recirculation of naive
lymphocytes through the peripheral
lymphoid organs, to which antigen is
carried from any site of infection
Lymph from most sites in the body is
returned to the Thoracic duct

T-CELLS
The Thymus provides the environment for
T-cell differentiation
Thymic epithelial cells produce a series of
peptide hormones which mostly seem
capable of promoting the appearance of Tcell differentiation markers.
Several have been well characterized
including Thymulin, Thymosin 1,
Thymic humoral factor and
Thymopoietin (hormon tsb)

T-CELLS
Activated T-cells proliferate in response to
cytokines
T-blasts expressed surface receptors for IL2 and proliferate in response to IL-2
IL-2 is single peptide (15.5kDa)
IL-2 receptors are not present on resting
cells but are synthesized within a few hours
after activation.

B-CELLS

B-lymphocyte precursors, pro-B-cells are

present among the islands of hematopoietic
cells in fetal liver by 8-9 weeks of gestation.
Production of B-cells by the liver wanes and is
mostly taken over by the bone marrow for the
remainder of life.
B-cells have different stages in their
development and a series of differentiation
markers associated with B-cell maturation

B-CELLS
Proliferation and maturation of B-cell
responses are mediated by cytokines
The activation of B-cells by Th cells leads to
upregulation of the surface receptor for IL-4
IL-2 and IL-13 contributes to Clonal
proliferation and expansion of the activated
B-cell population

Activation of B- and T-Lymphocytes

Lymph nodes are sites of activation of
lymphocytes by antigen.
Naive lymphocytes enter lymph nodes
continuously from the blood
When a lymphocyte with an appropriate
receptor binds to the trapped antigen it
ceases to recirculate and becomes
activated

Proses ini
terjadi di
kel. limfatik

B
Proliferasi&
diferensiasi
(cycle cell)
genetiknya

Sintesa DNA

Udah jadi sel

plasma
(bukan sel B
lg)

Activation of B- and T-Lymphocytes

Activated cells are called lymphoblasts,
they become proliferate and differentiate
into an effector- and memory- cells.
Clonal expansion & Clonal differentiation
Those lymphocytes (T- dan B-cells) have
the same receptor as their original ones.
B-receptor : 2 antigen recognized site
T-receptor : 1 antigen recognized site

Activation of B- and T-Lymphocytes

Effector cells :
B-cells
T-cells

Plasma cells
T-cytotoxic
T-Helper
T-inflammatory
T-cell receptor recognize only peptide
which is presented by MHC/HLA
molecules on the cell surface.

Major Histocompatibility Complex

MHC / HLA (Human Leucocyte Antigen)
is a protein which is synthesized in the
cell, present an antigen on the cell
surface which will be recognize by Tcell Receptor.
We can find MHC class I on the cell
surface of all cells except those
Erythrocytes and Thrombocytes
This protein can activate CD8+ T-cells

Major Histocompatibility Complex

MHC class II molecules are cell-surface
glycoproteins, that deliver peptides and
activate CD4+ T-cells
MHC class III : part of the Complement
system : C4, C2, Factor B and Isozyme
21-hydroxylase
MHC class IV : similar with those MHC
class I but has restricted distribution.

MHC kls I terdiri dari 4

sub unit microglobulin:
Mngkp 8-10 aa

Major Histocompatibility Complex

MHC class I and II have similar three
dimentional structure, although they have
sub-unit structure.
MHC cIass I consist of 3 loci (A,B,C) and
HLA class II consist of several region (DR,
DQ, DP, DO, DN etc.)
MHC molecules binds peptide and present
it on the cell surface, where they will be
recognize by T-cell receptors.

Relative Risk of HLA upon particular disease

(Certain disease associate with HLA antigen).

MHC class I molecules do not leave the

Endoplasmic Reticulum they bind peptides

Degradation and transport of antigens that bind

MHC class I molecules

The MHC class II associated invariant chain

delays peptide binding and targets MHC class II
molecules to the endosome (acidified intracellular
vesicles)

1. Immunosuppressant drugs

A. Inhibitors of Lymphocyte Gene Expression

to Reduce Inflammatory Response

Glucocorticoids

mechanism of action:
Multiple mechanisms are involved in the suppression of inflammation
by glucocorticoids.
Glucocorticoids inhibit the production by multiple cells of factors that
are critical in generating the inflammatory response.
As a result there is decreased release of vasoactive and
chemoattractive factors diminished secretion of lipolytic and
proteolytic enzymes decreased extravasation of leukocytes to areas of
injury and ultimately decreased fibrosis.
Glucocorticoids can also reduce expression of proinflammatory
cytokines such as COX-2 and NOS2.
Stresses such as injury, infection and disease result in the increased
production of cytokines a network of signaling molecules that
integrate actions of macrophages/monocytes, T lymphocytes and B
lymphocytes in mounting immune responses.

Therapeutic Uses:
Acute transplant rejection, graft-versus-host disease in
bonemarrow transplantation
Rheumatoid and other arthritides
Systemic lupus erythematosus
Systemic dermatomyositis, psoriasis and other skin
conditions
Asthma and other allergic disorders
Inflammatory bowel disease
Inflammatory ophthalmic diseases.

Adverse Effects:
Growth retardation in children
Avascular necrosis of bone,
Osteopenia
Increased risk of infection
Poor wound healing,
Cataracts
Hyperglycemia
Hypertension

B. Inhibitors of Lymphocyte Signaling to Prevent

Immune Cell Activation and Proliferation

Calcineurin Inhibitors:
1. Cyclosporine

mechanism of action:

Cyclosporine suppresses T-cell-dependent immune mechanisms

such as those underlying transplant rejection and some forms of
autoimmunity.
It preferentially inhibits antigen-triggered signal transduction in T
lymphocytes, blunting expression of many lymphokines including IL-2 and
the expression of antiapoptotic proteins.
Cyclosporine forms a complex with cyclophilin, a cytoplasmic receptor
protein present in target cells. This complex binds to calcineurin, inhibiting
Ca2+-stimulated dephosphorylation of the cytosolic component of nuclear
factor for activated T-cells (NFAT).

Pharmacokinetics:

Cyclosporine can be given orally or I.V.

Its oral bioavailability is low (about 30%).
Food decreases its absorption.
It is metabolized by CYP3A which may result in drug-drug
interactions.
Inactive metabolites are excreted mainly in bile and then in
feces but minimally in urine.
Plasma half life is about 24 hrs.

Therapeutic Uses:
Kidney, liver, heart, and other organ
transplantation
Rheumatoid arthritis and psoriasis
Early engraftment
Extending kidney graft survival
Cardiac and liver transplantation
Atopic dermatitis.

2. Tacrolimus:
Tacrolimus (PROGRAF, FK506) is a macrolide antibiotic
produced by Streptomyces tsukubaensis.

Mechanism of Action:

Like cyclosporine, tacrolimus inhibits Tcell activation by

inhibiting calcineurin.
Tacrolimus binds to an intracellular protein FK506-binding
protein-12 (FKBP-12) an immunophilin structurally related to
cyclophilin
A complex of tacrolimus-FKBP-12, Ca2+, calmodulin, and
calcineurin then forms, and calcineurin phosphatase activity
is inhibited. As described for cyclosporine the inhibition of
phosphatase activity prevents dephosphorylation and
nuclear translocation of NFAT and inhibits T-cell activation.

Pharmacokinetics:
Tacrolimus can be given orally or I.V. It is 99% metabolized
in liver by CYP3A and has a plasma half life of 7-8 hrs.
Therapeutic Uses:
Prophylaxis of solid-organ allograft rejection, kidney
transplantation, pediatric liver transplantation.
Adverse effects:
Nephrotoxicity, neurotoxicity (tremor, headache, motor
disturbances and seizures), GI complaints, hypertension,
hyperkalemia, hyperglycemia, and diabetes

Mammalian Target of Rapamycin (mTOR)

Inhibitors.
Sirolimus

Sirolimus (rapamycin; RAPAMUNE) is a macrocyclic

lactone produced by Streptomyces hygroscopicus.
mechanism of action:

Sirolimus inhibits T-lymphocyte activation and proliferation downstream

of the IL-2 and other T-cell growth factor receptors.
Sirolimus requires formation of a complex with an immunophilin in this
case FKBP-12. However, the sirolimus-FKBP-12 complex does
not affect calcineurin activity.
It binds to and inhibits a protein kinase designated mammalian target of
rapamycin (mTOR) which is a key enzyme in cell-cycle progression.
Inhibition of mTOR blocks cell-cycle progression at the G1 to S- phase
transition.

Pharmacokinetics:
Oral bioavailability is 15%. Fatty meal decreases its bioavailability.
Protein binding is 40-45% mainly with albumin. It is extensively
metabolized in liver by CYP3A4. Sirolimus is excreted 91% in feces
and only 2.5% in urine. Plasma half life is 62 hrs.
Therapeutic Uses:
Organ transplant inhibitor, graft rejection, incorporated into stents
to inhibit local cell proliferation and blood vessel occlusion.
Adverse Effects:
Dose-dependent increase in serum cholesterol and triglycerides,
impaired renal function, prolong delayed graft function, Lymphocele,
anemia, leukopenia

C. Cytotoxic Agents to Reduce Lymphocyte

Proliferation

Antimetabolites:
1. Mycophenolate Mofetil

mechanism of action:

Mycophenolate mofetil is a prodrug that is rapidly hydrolyzed to the

active drug, mycophenolic acid (MPA), a selective, noncompetitive and
reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), an
important enzyme in the de novo pathway of guanine nucleotide synthesis.
B and T lymphocytes are highly dependent on this pathway for cell
proliferation while other cell types can use salvage pathways; MPA therefore
selectively inhibits lymphocyte proliferation and functions including antibody
formation, cellular adhesion, and migration.

Pharmacokinetics:

Mycophenolate mofetil undergoes rapid and complete

metabolism to MPA after oral or intravenous administration. MPA, in
turn is metabolized to the inactive phenolic glucuronide MPAG.
Most (87%) is excreted in the urine as MPA.

Therapeutic Uses:

Prophylaxis of transplant rejection, renal transplantation

Adverse effects:

Leukopenia, diarrhoea, and vomiting, sepsis associated with

cytomegalovirus,

Alkylating Agents:
Cyclophosphamide

mechanism of action:

Alkylating agents introduce alkyl groups by forming covalent bonds

with nucleophilic moieties such as phosphate, sulfhydryl, hydroxyl,
carboxyl, amino and imidazole groups present in DNA or RNA. By
cross linking in between the strands of DNA they prevent the cell
division and protein synthesis.
These drugs are most destructive to rapidly proliferating tissues and
appear to cause cell death when they tend to divide.
The cytotoxicity of these drugs correlates with the degree of DNA
alkylation.

Therapeutic Uses:

Autoimmune disorders (including systemic lupus

erythematosus), in patients with acquired factor XIII
antibodies and bleeding syndromes, autoimmune
hemolytic anemia

Adverse effects:

graftversus-host disease syndrome, nausea, vomiting,

cardiac
toxicity and electrolyte disturbances

D. Cytokine Inhibitors

TNF- and IL-1 are proinflammatory cytokines implicated in pathogenesis of

rheumatoid arthritis. Il-2 binds to activated T-lymphocytes and promotes
their proliferation.

TNF- Inhibitors
Activated cytotoxic TH1 cells, macrophages and cells secrete TNF-
that to TNF receptors (TNFR1 or TNFR2) present on fibroblasts, neutrophils
and vascular endothelial cells. Besides these, there are soluble form of TNF receptor present in serum and synovial fluid.
Activation of TNF- result in the release of cytokines IL-1, IL-6 and
adhesion molecules that promote leukocyte activation and trafficking
(migration).
e.g . Etanercept, Infliximab, Adalimumab

D. Antibodies Against Specific Immune Cell

Molecules

Antithymocyte Globulin (ATG)

Antithymocyte globulin is a purified gamma globulin from the serum
of rabbits immunized with human thymocytes

Mechanism of Action:

Antithymocyte globulin contains cytotoxic antibodies that bind to CD2, CD3,

CD4, CD8, CD11a, CD18, CD25, CD44, CD45, and HLA class I and II
molecules on the surface of human T lymphocytes. The antibodies deplete
circulating lymphocytes by direct cytotoxicity (both complement and cellmediated) and block lymphocyte function by binding to cell surface
molecules involved in the regulation of cell function.

2. Immunostimulant drugs

In contrast to immunosuppressive agents

that inhibit the immune response in
transplant rejection and autoimmunity, a
few immunostimulatory drugs have been
developed with applicability to infection,
immunodeficiency, and cancer. These
works on cellular as well as humoral
immune system or both

I. Bacillus Calmette-Guerin (BCG):

Live bacillus Calmette-Guerin (BCG) is an attenuated, live culture
of the bacillus of Calmette and Guerin strain of Mycobacterium
bovis.

Mechanism of action:

Induction of a granulomatous reaction at the site of administration.

Therapeutic uses:

Treatment and prophylaxis of carcinoma of the urinary bladder,

prophylaxis of primary and recurrent stage Ta and/or T1 papillary
tumors after transurethral resection.

Adverse effects:

Hypersensitivity, shock, fever, malaise, and immune complex

disease

II. Levamisole:
Levamisole (ERGAMISOL) was synthesized originally as an
anthelmintic but appears to restore depressed immune function of
B lymphocytes, T lymphocytes, monocytes and macrophages

Therapeutic uses:
Adjuvant therapy with 5-fluorouracil after surgical resection in
patients with Dukes stage C colon cancer, agranulocytosis.

Adverse effects:
Flu-like symptoms, allergic manifestation, nausea and muscle
pain

III. Thalidomide:
Mechanism of action:
Thalidomide has been reported to decrease circulating
TNF- in patients with erythema nodosum leprosum, but
to increase it in patients who are HIV-seropositive.
Alternatively, it has been suggested that the drug affects
angiogenesis.
Therapeutic uses:
Severe, refractory rheumatoid arthritis 4,15,18.
Adverse effects:
Teratogenicity

IV. Recombinant Cytokines

V. Isoprinosine:
Mechanism of action:

Isoprinosine has been shown to augment production of cytokines such

as IL-1, IL-2 and IFN-. It increases proliferation of lymphocytes in
response to mitogenic or antigenic stimuli, increases active T-cell
rosettes and induces T-cell surface markers on prothymocytes.

Therapeutic uses:

Herpes simplex infections, subacute sclerosing panencephalitis, acute

viral encephalitis caused by herpes simplex, Epstein-Barr and measles
viruses

Adverse effects:

Minor CNS depressant, transient nausea and rise of uric acid in serum
and urine

VI. Immunocynin:
It is a stable form of haemocynin, a non- haeme, oxygen
carrying, copper containing protein found in arthropods
and molluses.

Therapeutic uses:
Urinary bladder cancer.
Adverse effects:
Rare-mild fever

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